Extremely cold and hot temperatures increase the risk of ischaemic heart disease mortality : epidemiological evidence from China

Objective: To examine the effects of extremely cold and hot temperatures on ischaemic heart disease (IHD) mortality in five cities (Beijing, Tianjin, Shanghai, Wuhan and Guangzhou) in China; and to examine the time relationships between cold and hot temperatures and IHD mortality for each city. Design: A negative binomial regression model combined with a distributed lag non-linear model was used to examine city-specific temperature effects on IHD mortality up to 20 lag days. A meta-analysis was used to pool the cold effects and hot effects across the five cities. Patients: 16 559 IHD deaths were monitored by a sentinel surveillance system in five cities during 2004–2008. Results: The relationships between temperature and IHD mortality were non-linear in all five cities. The minimum-mortality temperatures in northern cities were lower than in southern cities. In Beijing, Tianjin and Guangzhou, the effects of extremely cold temperatures were delayed, while Shanghai and Wuhan had immediate cold effects. The effects of extremely hot temperatures appeared immediately in all the cities except Wuhan. Meta-analysis showed that IHD mortality increased 48% at the 1st percentile of temperature (extremely cold temperature) compared with the 10th percentile, while IHD mortality increased 18% at the 99th percentile of temperature (extremely hot temperature) compared with the 90th percentile. Conclusions: Results indicate that both extremely cold and hot temperatures increase IHD mortality in China. Each city has its characteristics of heat effects on IHD mortality. The policy for response to climate change should consider local climate–IHD mortality relationships.

Bcl-2 genes and growth factors in the pathology of ischaemic acute renal failure

For the past decade, an attempt has been made by many research groups to define the roles of the growing number of Bcl-2 gene family proteins in the apoptotic process. The Bcl-2 family consists of pro-apoptotic (or cell death) and anti-apoptotic (or cell survival) genes and it is the balance in expression between these gene lineages that may determine the death or survival of a cell. The majority of studies have analysed the role/s of the Bcl-2 genes in cancer development. Equally important is their role in normal tissue development, homeostasis and non-cancer disease states. Bcl-2 is crucial for normal development in the kidney, with a deficiency in Bcl-2 producing such malformation that renal failure and death result. As a corollary, its role in renal disease states in the adult has been sought. Ischaemia is one of the most common causes of both acute and chronic renal failure. The section of the kidney that is most susceptible to ischaemic damage is the outer zone of the outer medulla. Within this zone the proximal tubules are most sensitive and often die by necrosis or desquamate. In the distal nephron, apoptosis is the more common form of cell death. Recent results from our laboratory have indicated that ischaemia-induced acute renal failure is associated with up-regulation of two anti-apoptotic Bcl-2 proteins (Bcl-2 and Bcl-XL) in the damaged distal tubule and occasional up-regulation of Bax in the proximal tubule. The distal tubule is a known reservoir for several growth factors important to renal growth and repair, such as insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF). One of the likely possibilities for the anti-cell death action of the Bcl-2 genes is that the protected distal cells may be able to produce growth factors that have a further reparative or protective role via an autocrine mechanism in the distal segment and a paracrine mechanism in the proximal cells. Both EGF and IGF-1 are also up-regulated in the surviving distal tubules and are detected in the surviving proximal tubules, where these growth factors are not usually synthesized. As a result, we have been using in vitro methods to test: (i) the relative sensitivities of renal distal and proximal epithelial cell populations to injury caused by mechanisms known to act in ischaemia-reperfusion; (ii) whether a Bcl-2 anti-apoptotic mechanism acts in these cells; and (iii) whether an autocrine and/or paracrine growth factor mechanism is initiated. The following review discusses the background to these studies as well as some of our preliminary results.

In vivo and in vitro models demonstrate a role for caveolin-1 in the pathogenesis of ischaemic acute renal failure

Caveolae and their proteins, the caveolins, transport macromolecules; compartmentalize signalling molecules; and are involved in various repair processes. There is little information regarding their role in the pathogenesis of significant renal syndromes such as acute renal failure (ARF). In this study, an in vivo rat model of 30 min bilateral renal ischaemia followed by reperfusion times from 4 h to 1 week was used to map the temporal and spatial association between caveolin-1 and tubular epithelial damage (desquamation, apoptosis, necrosis). An in vitro model of ischaemic ARF was also studied, where cultured renal tubular epithelial cells or arterial endothelial cells were subjected to injury initiators modelled on ischaemia-reperfusion (hypoxia, serum deprivation, free radical damage or hypoxia-hyperoxia). Expression of caveolin proteins was investigated using immunohistochemistry, immunoelectron microscopy, and immunoblots of whole cell, membrane or cytosol protein extracts. In vivo, healthy kidney had abundant caveolin-1 in vascular endothelial cells and also some expression in membrane surfaces of distal tubular epithelium. In the kidneys of ARF animals, punctate cytoplasmic localization of caveolin-1 was identified, with high intensity expression in injured proximal tubules that were losing basement membrane adhesion or were apoptotic, 24 h to 4 days after ischaemia-reperfusion. Western immunoblots indicated a marked increase in caveolin-1 expression in the cortex where some proximal tubular injury was located. In vitro, the main treatment-induced change in both cell types was translocation of caveolin-1 from the original plasma membrane site into membrane-associated sites in the cytoplasm. Overall, expression levels did not alter for whole cell extracts and the protein remained membrane-bound, as indicated by cell fractionation analyses. Caveolin-1 was also found to localize intensely within apoptotic cells. The results are indicative of a role for caveolin-1 in ARF-induced renal injury. Whether it functions for cell repair or death remains to be elucidated.

The pathophysiology of ischaemic stroke : considerations for emergency department advanced practice nursing

Stroke is the fourth most important cause of death in Singapore. Its major predisposing factors include hypertension, type 2 diabetes mellitus and hyperlipidaemia; all modifiable diseases if treated early. However, with Singapore’s elderly population, the risk and rates of stroke are ever increasing. The nature of a stroke can be categorised as eitherh aemorrhagic or ischaemic; the former caused by arterial rupture, the latter by arterial blockage; both can be devastating in their prognosis and outcome. This paper will discuss the pathophysiology of ischaemic stroke while identifying some of the key features of ischaemia on different areas of the brain relative to the artery that feeds them. Thoughts for Emergency Department advanced practice nursing will also be discussed.

Association between biomechanical structural stresses of atherosclerotic carotid plaques and subsequent ischaemic cerebrovascular events - A longitudinal in vivo magnetic resonance imaging-based finite element study

Background: High-resolution magnetic resonance (MR) imaging has been used for MR imaging-based structural stress analysis of atherosclerotic plaques. The biomechanical stress profile of stable plaques has been observed to differ from that of unstable plaques; however, the role that structural stresses play in determining plaque vulnerability remains speculative. Methods: A total of 61 patients with previous history of symptomatic carotid artery disease underwent carotid plaque MR imaging. Plaque components of the index artery such as fibrous tissue, lipid content and plaque haemorrhage (PH) were delineated and used for finite element analysis-based maximum structural stress (M-C Stress) quantification. These patients were followed up for 2 years. The clinical end point was occurrence of an ischaemic cerebrovascular event. The association of the time to the clinical end point with plaque morphology and M-C Stress was analysed. Results: During a median follow-up duration of 514 days, 20% of patients (n=12) experienced an ischaemic event in the territory of the index carotid artery. Cox regression analysis indicated that M-C Stress (hazard ratio (HR): 12.98 (95% confidence interval (CI): 1.32-26.67, pZ0.02), fibrous cap (FC) disruption (HR: 7.39 (95% CI: 1.61e33.82), p Z 0.009) and PH (HR: 5.85 (95% CI: 1.27e26.77), p Z 0.02) are associated with the development of subsequent cerebrovascular events. Plaques associated with future events had higher M-C Stress than those which had remained asymptomatic (median (interquartile range, IQR): 330 kPa (229e494) vs. 254 kPa (166-290), p Z0.04). Conclusions: High biomechanical structural stresses, in addition to FC rupture and PH, are associated with subsequent cerebrovascular events.

Stress analysis of carotid atheroma in a transient ischaemic attack patient using the MRI-based fluid-structure interaction method

Rupture of atherosclerotic plaque is a major cause of mortality. Plaque stress analysis, based on patient-specific multisequence in vivo MRI, can provide critical information for the understanding of plaque rupture and could eventually lead to plaque rupture prediction. However, the direct link between stress and plaque rupture is not fully understood. In the present study, the plaque from a patient who recently experienced a transient ischaemic attack (TIA) was studied using a fluid-structure interaction method to quantify stress distribution in the plaque region based on in vivo MR images. The results showed that wall shear stress is generally low in the artery with a slight increase at the plaque throat owing to minor luminal narrowing. The oscillatory shear index is much higher in the proximal part of the plaque. Both local wall stress concentrations and the relative stress variation distribution during a cardiac cycle indicate that the actual plaque rupture site is collocated with the highest rupture risk region in the studied patient.

Levosimendan in patients with ischaemic heart disease

Levosimendan is a drug developed for the treatment of heart failure. Its mechanism of action includes calcium sensitization of contractile proteins and the opening of ATP-sensitive potassium channels. The combination of positive inotropy with possible anti-ischaemic effects via potassium channel opening may offer benefits in comparison with currently available intravenous inotropes, which are contraindicated in patients with ongoing myocardial ischaemia. The active levosimendan metabolite OR-1896 significantly prolongs the duration of the haemodynamic effects of levosimendan. The aims of the present study were to investigate: 1) the clinical effects and safety of intravenous and oral levosimendan and 2) the pharmacodynamics and pharmacokinetics of intravenous and oral levosimendan and its metabolites in patients with ischaemic heart disease. Levosimendan was administered intravenously or orally in four studies to 557 patients with ischaemic heart disease with or without concomitant heart failure. One study included patients with acute myocardial infarction, while the other three studies included stable ischaemic patients. Non-invasive haemodynamic measurements were used in all studies, and blood samples for pharmacokinetics were drawn in three studies. Safety was followed by ECG recordings, adverse event inquiries and laboratory assessments. Intravenous levosimendan, administered as a 6-hour infusion did not cause clinically significant hypotension or ischaemia in comparison with placebo and reduced worsening heart failure and short- and long-term mortality. Increase in incidence of hypotension and ischaemia was seen only with the highest dose (0.4 µg/kg/min). Both intravenous and oral levosimendan possessed a moderate positive inotropic effect. Vasodilatory effect was more pronounced with intravenous levosimendan. A chronotropic effect was seen in all studies; however, it was not accompanied by any increase in arrhythmic events. The formation of levosimendan metabolites after oral dosing increased linearly with the daily dose of the parent drug, leading to increased inotropic and chronotropic response. Levosimendan was well tolerated in all studies. In conclusion, levosimendan was safe and effective in the treatment of patients with acute or chronic ischaemia. The risk-benefit ratio of intravenous levosimendan is favourable up to the dose of 0.2 µg/kg/min. The daily dose of oral levosimendan in patients with ischaemic heart failure should not exceed 4 mg due to an increase in chronotropic response.

Ischaemic concentrations of lactate increase TREK1 channel activity by interacting with a single histidine residue in the carboxy terminal domain

Key points The physiological metabolite, lactate and the two-pore domain leak potassium channel, TREK1 are known neuroprotectants against cerebral ischaemia. However, it is not known whether lactate interacts with TREK1 channel to provide neuroprotection. In this study we show that lactate increases TREK1 channel activity and hyperpolarizes CA1 stratum radiatum astrocytes in hippocampal slices. Lactate increases open probability and decreases longer close time of the human (h)TREK1 channel in a concentration dependent manner. Lactate interacts with histidine 328 (H328) in the carboxy terminal domain of hTREK1 channel to decrease its dwell time in the longer closed state. This interaction was dependent on the charge on H328. Lactate-insensitive mutant H328A hTREK1 showed pH sensitivity similar to wild-type hTREK1, indicating that the effect of lactate on hTREK1 is independent of pH change. AbstractA rise in lactate concentration and the leak potassium channel TREK1 have been independently associated with cerebral ischaemia. Recent literature suggests lactate to be neuroprotective and TREK1 knockout mice show an increased sensitivity to brain and spinal cord ischaemia; however, the connecting link between the two is missing. Therefore we hypothesized that lactate might interact with TREK1 channels. In the present study, we show that lactate at ischaemic concentrations (15-30mm) at pH7.4 increases TREK1 current in CA1 stratum radiatum astrocytes and causes membrane hyperpolarization. We confirm the intracellular action of lactate on TREK1 in hippocampal slices using monocarboxylate transporter blockers and at single channel level in cell-free inside-out membrane patches. The intracellular effect of lactate on TREK1 is specific since other monocarboxylates such as pyruvate and acetate at pH7.4 failed to increase TREK1 current. Deletion and point mutation experiments suggest that lactate decreases the longer close dwell time incrementally with increase in lactate concentration by interacting with the histidine residue at position 328 (H328) in the carboxy terminal domain of the TREK1 channel. The interaction of lactate with H328 is dependent on the charge on the histidine residue since isosteric mutation of H328 to glutamine did not show an increase in TREK1 channel activity with lactate. This is the first demonstration of a direct effect of lactate on ion channel activity. The action of lactate on the TREK1 channel signifies a separate neuroprotective mechanism in ischaemia since it was found to be independent of the effect of acidic pH on channel activity. Key points The physiological metabolite, lactate and the two-pore domain leak potassium channel, TREK1 are known neuroprotectants against cerebral ischaemia. However, it is not known whether lactate interacts with TREK1 channel to provide neuroprotection. In this study we show that lactate increases TREK1 channel activity and hyperpolarizes CA1 stratum radiatum astrocytes in hippocampal slices. Lactate increases open probability and decreases longer close time of the human (h)TREK1 channel in a concentration dependent manner. Lactate interacts with histidine 328 (H328) in the carboxy terminal domain of hTREK1 channel to decrease its dwell time in the longer closed state. This interaction was dependent on the charge on H328. Lactate-insensitive mutant H328A hTREK1 showed pH sensitivity similar to wild-type hTREK1, indicating that the effect of lactate on hTREK1 is independent of pH change.

Mixed methods feasibility study for a trial of blood pressure telemonitoring for people who have had stroke/transient ischaemic attack (TIA).

Background Good blood pressure (BP) control reduces the risk of recurrence of stroke/transient ischaemic attack (TIA). Although there is strong evidence that BP telemonitoring helps achieve good control, none of the major trials have considered the effectiveness in stroke/TIA survivors. We therefore conducted a feasibility study for a trial of BP telemonitoring for stroke/ TIA survivors with uncontrolled BP in primary care. Method Phase 1 was a pilot trial involving 55 patients stratified by stroke/TIA randomised 3:1 to BP telemonitoring for 6 months or usual care. Phase 2 was a qualitative evaluation and comprised semi-structured interviews with 16 trial participants who received telemonitoring and 3 focus groups with 23 members of stroke support groups and 7 carers. Results Overall, 125 patients (60 stroke patients, 65 TIA patients) were approached and 55 (44%) patients were randomised including 27 stroke patients and 28 TIA patients. Fifty-two participants (95%) attended the 6-month follow-up appointment, but one declined the second daytime ambulatory blood pressure monitoring (ABPM) measurement resulting in a 93% completion rate for ABPM − the proposed primary outcome measure for a full trial. Adherence to telemonitoring was good; of the 40 participants who were telemonitoring, 38 continued to provide readings throughout the 6 months. There was a mean reduction of 10.1 mmHg in systolic ABPM in the telemonitoring group compared with 3.8 mmHg in the control group, which suggested the potential for a substantial effect from telemonitoring. Our qualitative analysis found that many stroke patients were concerned about their BP and telemonitoring increased their engagement, was easy, convenient and reassuring Conclusions A full-scale trial is feasible, likely to recruit well and have good rates of compliance and follow-up.

Early biomarkers to predict grade of encephalopathy following hypoxic ischaemic injury

The standard early markers for identifying and grading HIE severity, are not sufficient to ensure all children who would benefit from treatment are identified in a timely fashion. The aim of this thesis was to explore potential early biomarkers of HIE. Methods: To achieve this a cohort of infants with perinatal depression was prospectively recruited. All infants had cord blood samples drawn and biobanked, and were assessed with standardised neurological examination, and early continuous multi-channel EEG. Cord samples from a control cohort of healthy infants were used for comparison. Biomarkers studied included; multiple inflammatory proteins using multiplex assay; the metabolomics profile using LC/MS; and the miRNA profile using microarray. Results: Eighty five infants with perinatal depression were recruited. Analysis of inflammatory proteins consisted of exploratory analysis of 37 analytes conducted in a sub-population, followed by validation of all significantly altered analytes in the remaining population. IL-6 and IL-6 differed significantly in infants with a moderate/severely abnormal vs. a normal-mildly abnormal EEG in both cohorts (Exploratory: p=0.016, p=0.005: Validation: p=0.024, p=0.039; respectively). Metabolomic analysis demonstrated a perturbation in 29 metabolites. A Cross- validated Partial Least Square Discriminant Analysis model was developed, which accurately predicted HIE with an AUC of 0.92 (95% CI: 0.84-0.97). Analysis of the miRNA profile found 70 miRNA significantly altered between moderate/severely encephalopathic infants and controls. miRNA target prediction databases identified potential targets for the altered miRNA in pathways involved in cellular metabolism, cell cycle and apoptosis, cell signaling, and the inflammatory cascade. Conclusion: This thesis has demonstrated that the recruitment of a large cohortof asphyxiated infants, with cord blood carefully biobanked, and detailed early neurophysiological and clinical assessment recorded, is feasible. Additionally the results described, provide potential alternate and novel blood based biomarkers for the identification and assessment of HIE.

A comparative analysis of the SF-12 and the SF-36 among ischaemic heart disease patients.

This paper investigated whether the SF-12 could replace the SF-36 in the measurement of health status among ischaemic heart disease patients. The SF-36 and SF-12 were administered to 105 cardiac patients. The SF-36 summary scores were strongly correlated and similar to the SF-12 summary scores. Also, the SF-12 scores were as powerful as the SF-36 summary scores in discriminating between subgroups of patients categorized according to their self-reported health status or angina classification. It is suggested that when there is a need to collect routine information about cardiac patients' general physical and mental health, the SF-12 is preferable to the SF-36 because of its brevity and acceptability to patients.

Measuring the health-related quality of life of people with ischaemic heart disease.

Objectives—To inform researchers and clinicians about the most appropriate generic and disease specific measures of health related quality of life for use among people with ischaemic heart disease. Methods—MEDLINE and BIDS were searched for research papers which contained a report of at least one of the three most common generic instruments or at least one of the five disease specific instruments used with ischaemic heart disease patients. Evidence for the validity, reliability, and sensitivity of these instruments was critically appraised. Results—Of the three generic measures—the Nottingham health profile, sickness impact profile, and short form 36 (SF-36)—the SF-36 appears to offer the most reliable, valid, and sensitive assessment of quality of life. However, a few of the SF-36 subscales lack a sufficient degree of sensitivity to detect change in a patient’s clinical condition. According to the best available evidence, the quality of life after myocardial infarction questionnaire should be preferred to the Seattle angina questionnaire, the quality of life index cardiac version, the angina pectoris quality of life questionnaire, and the summary index. Overall, research on disease specific measures is sparse compared to the number of studies which have investigated generic measures. Conclusions—An assessment of the quality of life of people with ischaemic heart disease should comprise a disease specific measure in addition to a generic measure. The SF-36 and the quality of life after myocardial infarction questionnaire (version 2) are the most appropriate currently available generic and disease specific measures of health related quality of life, respectively. Further research into the measurement of health related quality of life of people with ischaemic heart disease is required in order to address the problems (such as lack of sensitivity to detect change) identified by the review.